Nalidixic Acid

Approved Indications:

• Uncomplicated Urinary Tract Infections (UTIs):
• Treatment of acute or chronic UTIs caused by susceptible strains of gram-negative organisms, particularly Escherichia coli, Enterobacter spp., Klebsiella spp., and Proteus spp.
• Bacteriuria Management:
• Short- or long-term treatment of asymptomatic bacteriuria due to susceptible organisms when treatment is deemed necessary.

Clinically Accepted (Off-Label) Uses:

• Typhoid and Paratyphoid Fever (limited use):
• Occasionally used in the past in resource-limited settings, but largely replaced by newer quinolones and cephalosporins due to resistance concerns.

Note: Nalidixic acid is not effective against Pseudomonas aeruginosa, anaerobic bacteria, or gram-positive organisms.

Route of Administration: Oral (Tablets or Suspension)

Adults:

• Usual Dose: 1 gram orally every 6 hours (total: 4 grams/day)
• Duration: Typically 7–14 days depending on infection severity and clinical response

Children (≥3 months of age):

• Dose: 55 mg/kg/day orally in 4 divided doses (every 6 hours)
• Maximum daily dose: 4 grams
• Duration: 7–14 days; adjust based on clinical response

Pediatrics (<3 months):

• Contraindicated due to risk of hemolytic anemia and potential for CNS toxicity

Elderly:

• Use with caution due to age-related renal function decline.
• Monitor renal function and adjust dose if necessary.

Renal Impairment:

• Use cautiously; dose adjustment may be needed in moderate to severe renal impairment (CrCl <30 mL/min).
• Monitor for drug accumulation and neurotoxicity.

Hepatic Impairment:

• No specific dosage adjustments established, but caution is advised in moderate to severe hepatic dysfunction.

Nalidixic acid is a first-generation quinolone antimicrobial that acts by inhibiting bacterial DNA gyrase, an essential enzyme involved in DNA replication, transcription, and repair. By blocking DNA gyrase (topoisomerase II), the drug prevents the supercoiling of bacterial DNA, leading to inhibition of DNA synthesis and cell death. Its bactericidal effect is concentration-dependent and primarily targets gram-negative urinary pathogens. Unlike newer fluoroquinolones, it lacks activity against anaerobes and gram-positive bacteria.

• Absorption: Rapidly and well absorbed after oral administration
• Bioavailability: Approximately 96–98%
• Peak Plasma Concentration: Achieved within 1–2 hours of dosing
• Distribution: Concentrates well in the urine; minimal distribution to other tissues
• Protein Binding: 90–95%
• Metabolism: Primarily hepatic metabolism into active and inactive metabolites (e.g., hydroxy-nalidixic acid)
• Half-life: 1 to 2.5 hours (may be prolonged in renal dysfunction)
• Excretion: Primarily renal (via glomerular filtration and tubular secretion), with ~80–90% of the dose excreted in urine as parent drug and metabolites
• Onset of Action: Within a few hours
• Duration of Action: 4 to 6 hours

• Pregnancy:
  FDA Category C
  Animal studies have shown adverse fetal effects (e.g., cartilage toxicity), and there are no well-controlled studies in pregnant women. Should be used only if potential benefits justify the risks.
• Lactation:
  Excreted into breast milk. Due to risk of hemolysis and other adverse effects in nursing infants, use is not recommended during breastfeeding, especially in neonates or infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

• Primary Class: Antibacterial
• Subclass: Quinolone (non-fluorinated, first-generation quinolone)

• Hypersensitivity to nalidixic acid or other quinolones
• Age under 3 months
• History of seizures or seizure disorders
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Pregnancy (use only if clearly needed)
• Breastfeeding

• Seizures: May lower seizure threshold; avoid in patients with epilepsy or CNS disorders.
• CNS Effects: Headache, visual disturbances, dizziness, and hallucinations may occur, especially at high doses or in renal impairment.
• Hemolytic Anemia: Reported in patients with or without G6PD deficiency; monitor blood counts.
• Photosensitivity: Patients should avoid excessive sunlight or UV exposure.
• Crystalluria: Encourage adequate hydration to prevent crystalluria and nephrotoxicity.
• Hepatic Dysfunction: Use cautiously in patients with liver impairment.
• Tendon Effects: Though rare with nalidixic acid, tendinitis and tendon rupture are class-related risks for quinolones.

Common (≥1%):

• Gastrointestinal:
• Nausea, vomiting, diarrhea, abdominal pain
• Central Nervous System:
• Dizziness, headache, drowsiness, visual disturbances
• Skin:
• Rash, photosensitivity reactions

Less Common / Serious:

• Seizures, hallucinations, confusion
• Hemolytic anemia, especially in G6PD deficiency
• Hepatotoxicity
• Crystalluria or nephrotoxicity
• Intracranial hypertension (rare)
• Tendon rupture (very rare)

• Antacids (containing aluminum, magnesium, calcium):
• Decrease absorption of nalidixic acid; separate by at least 2 hours
• Warfarin:
• May potentiate anticoagulant effects → increased INR; monitor closely
• Sulfonylureas (e.g., glibenclamide):
• Risk of hypoglycemia; monitor blood glucose levels
• Probenecid:
• May decrease renal excretion, increasing nalidixic acid plasma levels
• CNS Stimulants or Theophylline:
• Additive CNS excitatory effects; increased seizure risk
• CYP450 Involvement:
• Primarily metabolized via hepatic pathways (non-CYP450 dependent); minor interactions with hepatic enzyme systems

• Discontinued or Limited Use in Some Regions:
  Due to increased resistance rates and availability of safer alternatives, nalidixic acid is rarely recommended as first-line therapy in updated guidelines from WHO and various national antimicrobial stewardship programs.
• Pediatric Caution Reinforced:
  Increased emphasis on avoiding use in neonates and children under 3 months due to CNS toxicity risks.
• Shift to Fluoroquinolones:
  Clinical use largely replaced by fluoroquinolones (e.g., ciprofloxacin) in urinary infections due to broader spectrum and improved pharmacokinetics.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Permitted Range: 15°C to 30°C
• Humidity & Light: Protect from moisture and direct light
• Oral Suspension:
• Shake well before use
• Store tightly closed; do not refrigerate
• Discard unused suspension after 14 days
• Tablets: Keep in original container, away from excess heat and moisture
• Handling: Do not use if tablets are discolored or if suspension changes consistency